tbuckley/cabot-search huggingface dataset:
A multicenter, open-label, single-arm, phase 1 dose-escalation study to evaluate the safety, tolerability, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1.
Authors: Xiaojie Hu, Kang Zeng, Zhongyuan Xu, Wenbin Li, Changxing Li, Zhuang Kang, Shenglan Li, Ai-Min Hui, Zhuli Wu, Xin Huang, Pu Han, Ben Li, Xiaoxi Lin
Journal: Journal of Clinical Oncology (2022)

3011 Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease that increases susceptibility to malignant tumors. Up to 50% of patients with NF1 present with plexiform neurofibroma (PN). Surgery, a common treatment strategy for patients with PN, has limited efficacy. NF1 is caused by mutations in the gene that encodes neurofibromin; the NF1 mutation then leads to tumorigenesis via dysregulation of the Ras/Raf/MEK/ERK pathway. FCN-159 is anti-tumorigenic via highly potent, selective inhibition of MEK1/2. This study aims to assess the safety of FCN-159 in patients with NF1-related PN. Methods: This is a multicenter, open-label, single-arm, phase 1 dose-escalation and phase 2 dose-expansion study (NCT04954001). Patients with NF1-related PN that was not completely resectable or not suitable for surgery were enrolled in the study; they received FCN-159 monotherapy continuously in 28-day cycles. Here, we report safety and clinical efficacy data from adults enrolled in phase 1. Results: As of the data cutoff of December 1, 2021, 19 adults from 3 hospitals in China have been enrolled in the phase 1 dose-escalation study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. The most common neurofibroma-related complications were disfigurement and pain, occurring in 10 patients (52.6%) and 4 patients (21.1%) at baseline, respectively. Four patients experienced dose-limiting toxicity; G3 folliculitis was reported in 1 patient (16.7%) receiving the 8-mg dose and 3 (100%) patients receiving the 12-mg dose. The maximum tolerated dose was determined to be 8 mg. Study-drug-related treatment-emergent adverse events (TEAEs) were observed in all 19 patients (100%); the majority were grade 1 or 2 in severity. Nine (47.4%) patients reported grade 3 study drug-related TEAEs; 4 patients experienced paronychia and 5 experienced folliculitis, which were the most common causes of dose reduction (42.1%) and drug interruption (21.2%). One patient experienced a serious adverse event of rhegmatogenous retinal detachment, but this was considered unrelated to the study drug as it was preexisting at baseline. Of the 16 patients with at least 1 post-baseline tumor assessment, all (100%) had reduced tumor size and 6 (37.5%) had a reduction in tumor size of &gt; 20%. Three out of 6 patients with a second tumor assessment result had further tumor shrinkage; tumor volumes in the remaining 3 patients were similar to those at first assessment. The largest reduction in tumor size was 84.2%. Conclusions: Overall, FCN-159 at 8 mg is well tolerated, with easy to manage adverse events, and showed promising anti-neurofibroma activity in phase 1; this warrants further investigation in a phase 2 study on efficacy and safety in this indication. Clinical trial information: NCT04954001.
Weekend effect on TLS admission in patients with acute leukemia and lymphoma: Nationwide analysis of mortality, HD, demographics and health care utilization.
Authors: Khaldun Obeidat, Muhammad Junaid Tariq, Shweta Gupta
Journal: Journal of Clinical Oncology (2022)

e19582 Background: Tumor lysis syndrome (TLS) is a well-known complication of hematological malignancies including leukemia and lymphoma which can occur after chemotherapy or spontaneously, early recognition of TLS can be challenging sometimes. We attempted to evaluate the Weekend effect on TLS outcomes. Methods: Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) was queried to identify TLS admissions between 2016-2018 in patients with diagnosis of acute leukemia and lymphoma. We studied socio-demographic differences, all-cause mortality, acute renal failure and dialysis. Secondary outcomes included mean length of stay (LOS), mean total hospital charges (THC). Statistics were performed using the t-test, univariate and multinomial logistic regression. Results: A total 1595 TLS admissions were identified (51% in lymphoma and 49% in acute leukemia), weekend admissions were 14.4% of total admissions. There was no significant difference in the baseline characteristics between the 2 groups including mean age, sex, race, median household income national quartile for patient zip code, insurance, region of hospital and location/teaching status of the hospital. Total 195 (12%) patients died in the total study group; Mortality rate among patients with lymphoma was 16% while those with leukemia was 9%. Overall mortality rate among the Weekend group compared to weekday group was insignificantly higher (20% vs 11% with P = 0.11, aOR 1.4 CI 0.56-3.46 p = 0.53). Mortality in the Weekend group was significantly higher in patients with lymphoma (30% vs 13% P = 0.04) while in leukemia patients there was no significant weekend effect (8% vs 9% P = 0.83). Total 1170 patients developed acute renal failure (aOR 1.56 Cl 0.64-3.9 p 0.32) of which 30 required dialysis, none of them was admitted in the weekend group. Mean LOS for the whole cohort was 6.47 days and mean THC was $94,954 with no significant difference between the 2 groups. Conclusions: All-cause mortality was significantly higher in patients with TLS and lymphoma admitted on the weekend (p = 0.04) compared to weekday while no weekend effect was found in TLS admissions in leukemia. Further studies are needed to clarify if this higher mortality may be associated with delay in TLS diagnosis over weekend admissions in lymphoma patients.
Exploratory radiomic analysis of stage III non-small cell lung cancer CT images: Correlation with clinical-pathological characteristics.
Authors: Giulia Pasello, Alessandra Ferro, Elena Scagliori, Gisella Gennaro, Matilde Costa, Matteo Sepulcri, Marco Schiavon, Laura Bonanno, Stefano Frega, Francesca Caumo, Fiorella Calabrese, Federico Rea, Valentina Guarneri
Journal: Journal of Clinical Oncology (2022)

e20574 Background: Recent evidences have suggested potential applications of radiomics in early diagnosis, prognostic stratification and treatment outcome prediction of Non-Small Cell Lung Cancer (NSCLC) patients. The purpose of this study is to evaluate the ability of radiomic analysis to discriminate between different clinical-pathological conditions in patients with stage III NSCLC. Methods: Baseline CT studies from 59 patients with stage III NSCLC referred to our Institution from 2010 and 2020 were retrospectively reviewed, and the segmentation of the main lung lesion and the extraction of 517 radiomic features performed using a commercial software. The number of features was reduced to 46 by means of principal component analysis applied using the R package “RadAR” (Radiomics Analysis with R). The Kruskal-Wallis test was applied to all the radiomic features in order to evaluate which of them can discriminate between 7 clinical dichotomous characteristics: tumor stage, type, presence of mutation, treatment response, relapse free survival (RFS), smoking habit, patient outcome. P &lt; 0.05 means that there is a statistically significant difference between the two subgroups. Results: The median age at diagnosis was 69 years (range 43-83). Most patients were males (40/59 = 67.8%) and heavy smokers (36/59 = 61.0%). Adenocarcinoma was the most common histology (41/59 = 70.7%), while cases were almost equally splitted between stage IIIA (45.8%) and stage IIIB or IIIC (54.2%). Most selected radiomic features (29/46 = 63.0%) showed a statistically significant difference between patients with and without mutations. Ten (10/46 = 21.7%) radiomic features were associated with patient sex. Seven features (7/45 = 15.2%) were “sensitive” to the tumor clinical stage (stage IIIA vs. stage IIIB+IIIC), 4 (4/46 = 8.7%) to the histological type, and 2 (2/46 = 4.3%) to the patient outcome. None of the selected radiomic features was able to discriminate between responder and non-responder patients, current/previous smokers and never smokers, and patients with RFS lower than 12 months versus RFS equal or higher than 12 months. Conclusions: This preliminary analysis showed that radiomics has the potential of identifying mathematical features associated with clinical and histopathological characteristics in stage III NSCLC patients, which might feed multiparametric predictive models. Larger datasets and further analysis are necessary in order to confirm initial results.
Physical activity levels in patients with melanoma during treatment with immune checkpoint inhibitors: Fitbit results from the CAMP-IT trial.
Authors: Milan Kos, Laurien M. Buffart, Jan Willem de Groot, Hans M. Westgeest, Marye J. Boers-Sonderen, Hanneke W.M. Van Laarhoven, Martijn G.H. van Oijen
Journal: Journal of Clinical Oncology (2022)

e13610 Background: Wearable activity trackers offer possibilities to harness real-time patient data for predicting clinical outcomes in patients with cancer during treatment with immune checkpoint inhibitors (ICIs). As a first step towards this purpose, we aimed to assess the feasibility of using wearable activity trackers to objectively measure physical activity levels during the course of treatment. Methods: Patients with advanced melanoma, scheduled to receive treatment with ICIs were eligible to participate in the Comprehensive Ambulatory Monitoring Platform during ImmunoTherapy (CAMP-IT) trial. Participants were instructed to wear a Fitbit Versa 2.0 during waking hours for 12 weeks after start of immunotherapy. Feasibility of Fitbit use was assessed using predefined goals regarding compliance (&gt; 75% participants with &gt; 75% wear days) and acceptability (satisfaction score &gt; 75%). Weekly averages of daily steps were calculated. A valid wear week was defined as a week with a minimum of 4 valid wear days (&gt; 100 steps) including at least 1 weekend day. Linear mixed models were used to examine the changes in mean daily steps during 12 weeks after treatment initiation. We currently analyzed data of the first 30 of the 50 patients that will be included in the trial. Results: Of the 30 patients that were currently included 57% was female and mean age was 57,3 (SD 9,7). Forty percent had metastatic disease, and 30% received treatment with combination ICI therapy. Ninety-six percent of patients was compliant with Fitbit use. Moreover, Fitbit use was rated as satisfactory by 86% of patients. Mean steps per day in week 1 was 6728 (SD 3405). Mean daily steps per week did not change significantly over time during the observation period (b = -13,3 (95% CI: -85,7 - 59,1); p = 0.72). Conclusions: This is the first prospective study that reports on the use of consumer-grade wearable activity trackers to objectively measure physical activity in advanced melanoma patients during treatment with ICIs. Our results suggest that the use of wearable activity trackers in these patients is feasible and that treatment with ICI does not impact physical activity levels during the first 12 weeks. Future research should investigate whether our results hold true for specific subgroups (e.g., patients that receive combination ICI therapy). Clinical trial information: NL8827.
Cancer immunotherapy: Identifying cancer testis antigen peptides to enhance antitumor response.
Authors: Syed Mahdee Haque, Abdul-Rahman Salman, Hamdi Abdeen, Elizabeth Krieger, Masoud Manjili, Rehan Qayyum, Sosipatros Alexandros Boikos, Amir A. Toor
Journal: Journal of Clinical Oncology (2022)

e20022 Background: Cancer testis antigens (CTAs) are highly immunogenic, tissue-restricted proteins that may be over expressed in hematological malignancies. In this study, an in silico analysis of CTA-derived peptide presentation on HLA class I molecules is reported with an aim to identify putative CTA peptides with a high estimated binding affinity to known HLA class I molecules. Methods: Eighty unique HLA Class I alleles (HLA-A, B, and C), across 78 hematopoietic cell transplant recipients were computationally studied for their ability to bind peptides derived from three CTAs. The amino acid sequences of all three CTA proteins were obtained from UniProtKB. NetMHCPan-4.1 was utilized for in silico prediction of HLA class I binding affinities of the 9-mer peptides generated from these CTAs. Results: The CTA MAGE-A1 had 1202 unique peptides predicted to bind at least one HLA class I allele and 176 of these peptides were classified as strong binders (Rank &lt;0.5 and IC50&lt;500nM). Conversely, 71 unique HLA class 1 alleles were predicted to bind strongly to at least one MAGE-A1 derived peptide. The ability of different MAGE-A1 peptides to bind HLA varied considerably, e.g., peptide TSYVKVLEY, was predicted to bind strongly to 22 different HLA class I alleles. Similarly, 41 CTAG-1B-derived and 164 MAGE-A2-derived peptides were predicted to generate strong binders with at least one HLA class 1 allele. Conversely, 37 and 71 unique HLA class I alleles were predicted to bind strongly to at least one CTAG1B peptide and one MAGE-A1 peptide, respectively. CTAG1-B derived peptide FATPMEAEL and MAGE-A2-derived peptide FAHPRKLLM were predicted to bind strongly to 17 and 22 HLA class 1 alleles, respectively. In aggregate most patients presented multiple peptides across the 6 HLA class I molecules studied (Table). The number of strongly binding MAGE-A1 and CTAG-1B peptides from unique patients. Strong binding defined by Rank &lt;0.5 and IC50&lt;500nM. Conclusions: Most patients presented several CTA derived peptides, suggesting that the aggregate HLA presentation across the 6 classical HLA class I molecules will yield high odds of presentation of CTA expressed by target tissues. These HLA genotype-informed quantitative analyses raise the possibility that agents such as checkpoint inhibitors and immunomodulatory drugs may synergize with hypomethylating agents and augment CTA-directed T-cell responses.[Table: see text]
Phase 1 dose escalation study of MH048, a novel and non-covalent BTK inhibitor in patients with relapsed or refractory B-cell malignancies.
Authors: Guoqing Cao, Zhengming Jin, Yuhua Li, Liling Zhang, Junwei Shi, Jie Jin
Journal: Journal of Clinical Oncology (2022)

7547 Background: Despite impressive clinical response of covalent Bruton’s tyrosine kinase (BTK) inhibitors in multiple B cell malignancies, treatment failure often occurs through drug resistance most commonly due to BTK cysteine-481 (C481) mutation or intolerance due to off-target toxicities. We evaluated the safety, pharmacokinetics (PK) and preliminary antitumor efficacy of MH048, an orally bioavailable, potent, and reversible inhibitor of both wild type and C481S-mutant BTK, in selected patients with relapsed or refractory (R/R) B-cell malignancies. Methods: Eligible patients with R/R B-cell malignancies were enrolled in a Phase 1, multicenter, open-label, dose escalation study. The primary objectives were to assess the safety and tolerability of MH048, and to determine the maximal tolerated dose (MTD) and the recommended dose for expansion. The secondary objectives were to assess the PK profile and preliminary evidence of anti-tumor activity. Results: Twelve patients were treated with MH048 across six dose levels (5 mg, 15 mg, 45 mg, 90 mg, 135 mg, 200 mg QD) in fast state. No dose-limiting toxicities were observed and the MTD was not reached. The most common drug-related TEAEs (Any grade) that occurred in &gt; 2 patients were platelet count decrease (n=5), anemia (n=4), neutrophil count decrease (n=4), lipase increase (n=3), and white blood cell count decrease (n=3). Drug-related grade 3 TEAEs included platelet count decrease, neutrophil count decrease, lipase increase, and hypertension (one patient for each). Plasma exposure of MH048 and its active metabolite (M3) increased in a dose-proportional manner from 5 to 200 mg dose levels. Sign of efficacy was observed starting from 15 mg. Among eleven efficacy-evaluable patients (one patient in 200 mg cohort is yet to be evaluated), one complete response (CR) and four partial responses (PRs) were achieved in ≥90 mg cohorts, including patients with MZL (n=1, CR), MCL (n=2), SLL (n=1) and DLBCL (n=1). Of the two MCL patients with PRs, one was heavily pretreated including ibrutinib prior to the enrollment. The recommended doses for expansion were selected as 135 and 200 mg. Conclusions: MH048 was well-tolerated and efficacy in heavily pre-treated patients with B-cell malignancies was observed. Pharmacokinetics studies suggest once-daily dosing. The dose expansion study is ongoing at 135 and 200 mg QD for CLL and MCL patients. Clinical trial information: NCT04689308.
Restaging prostate-specific membrane antigen positron emission tomography/ computed tomography is associated with improved oncological outcome in men who underwent salvage radiation therapy for biochemically recurrent prostate cancer
Authors: D. Meijer, W.S.C. Eppinga, R.M. Mohede, B.G.L. Vanneste, P. Meijnen, O.W.M. Meijer, L.A. Daniels, R.C.N. Van Den Bergh, A.P. Lont, R.H. Ettema, F.H.K. Oudshoorn, P.J. Van Leeuwen, H.G. Van Der Poel, M.L. Donswijk, D.E. Oprea-Lager, E.E. Schaake, A.N. Vis
Journal: European Urology (2022)
EPEN-05. Adenosine receptor expression in paediatric ependymoma
Authors: Chelsea Spanoudakis, Rebecca Chapman, Simon Paine, Richard Grundy, Hester Franks, Timothy Ritzmann
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Paediatric ependymoma is associated with dismal outcomes. Whilst understanding of its underlying biology has advanced, there has been little progress in treatment and clinical outcomes. Acting through four G protein-coupled receptors (encoded by ADORA1, ADORA2A, ADORA2B and ADORA3), adenosine is a signalling molecule often present at high levels in tumours. Adenosine signalling can aid tumour proliferation and invasiveness via mechanisms including suppression of tumour-infiltrating immune cells. Adenosine receptors therefore represent a potential therapeutic target in paediatric ependymoma, however neither levels nor patterns of expression have been previously reported. We hypothesised that adenosine receptors would be expressed in paediatric ependymoma and that this expression would vary between molecular subgroups. METHODS: Three publicly available gene expression datasets were analysed for adenosine receptor expression using Kruskal-Wallis, Mann-Whitney U and chi-square tests. RNAscope assays for adenosine receptors and CD68 were then performed on ten full-face ependymoma FFPE sections from posterior fossa A (PFA1 and PFA2) tumours to understand patterns of expression within ependymomas with the highest levels of expression identified by the gene expression datasets. RESULTS: Statistically significant differences were identified between adenosine-related genes across ependymoma subgroups of differing anatomical origin (supratentorial ZFTA-positive versus posterior fossa A and B (PFA/PFB)), with median adenosine-related gene levels generally higher in the PFA subgroup. Particularly, ADORA1, 2A, 2B and 3 gene expression was higher in PFA tumours than other subgroups. Analysis of the ten cases demonstrated measurable expression of all four adenosine receptors by RNAscope and patterns in the distribution and relative levels of expression of the adenosine receptors across PFA1 and PFA2 tumours were described. CONCLUSION: Using two different techniques we demonstrated that adenosine receptors are expressed in paediatric ependymomas. There are significant differences in level of expression between tumour subgroups. Adenosine receptors therefore represent a potential therapeutic target which should be explored further.
Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: A multicenter, open-label, single-arm phase 2 study.
Authors: Lili Mao, Meiyu Fang, Yu Chen, Xue Bai, Jun Cao, Jing Lin, Peng Zhang, Ling Chen, Jiahui Xu, Jun Guo, Lu Si
Journal: Journal of Clinical Oncology (2022)

9525 Background: Anti-programed cell death-1 (PD-1) monotherapy is a part of the standard therapy for cutaneous melanoma but has demonstrated low efficacy in mucosal melanoma. This study evaluated the efficacy and safety of atezolizumab plus bevacizumab as a first-line therapy in patients with advanced mucosal melanoma. Methods: This multicenter, open-label, single-arm, phase 2 study utilized a Simon’s two-stage design. Atezolizumab (fixed-dose, 1200 mg) and bevacizumab (7.5 mg/kg) were administered by intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR), determined by the investigator per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), and safety with adverse events summarized using NCI-CTCAE v5.0. Results: In total, 43 patients were enrolled, including 20 (46.5%) with unresectable and 23 (53.5%) with metastatic mucosal melanoma. Median follow-up was 13.4 months at data cut-off (July 30, 2021). Forty patients were evaluable for response: In stage I analysis set (n=22), the best confirmed ORR according to RECIST v1.1 was 40.9% (9/22; 95% CI 20.7-63.7), including one CR and eight PRs. The ORR in the FAS population was 45.0% (95% CI, 29.3-61.5) (1 CR, 17 PRs) and the DCR was 65.0% (95% CI, 48.3-79.4). The median PFS was 8.2 months (95% CI, 2.7-9.6), the 6- and 12-month PFS rates were 53.4% (95% CI, 36.6-67.6) and 28.1% (95% CI, 14.2-43.9), respectively. The median OS was not reached (NR) (95% CI, 14.4-NR). The 6- and 12-month OS rates were 92.5% (95% CI, 78.5-97.5) and 76.0% (95% CI, 57.1-87.5), respectively. The median DOR was 12.5 months (95% CI, 5.5-NR). Overall, 90.7% (39/43) of patients experienced treatment-related adverse events, and 25.6% (11/43) experienced grade ≥ 3 events. Conclusions: Atezolizumab in combination with bevacizumab showed promising efficacy and a manageable safety profile in patients with advanced mucosal melanoma. Research Sponsor: Shanghai Roche Pharmaceuticals Ltd., China. Clinical trial information: NCT04091217.
MEDB-11. MYC overexpression and SMARCA4 loss in cerebellar granule cell precursors cooperate to drive medulloblastoma formation in mice
Authors: Carolin Göbel, Dörthe Holdhof, Melanie Schoof, Catena Kresbach, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30 % of cases carry genetic alterations in MYC, SMARCA4 or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional significance of SMARCA4 mutations and their suitability as a therapeutic target remain largely unclear. To address this issue, we combined an overexpression of MYC with a loss of SMARCA4 in cerebellar granule cell precursors. Cells were isolated from 7-day-old Math1-creERT2::Smarca4fl/fl pups after tamoxifen-induced loss of SMARCA4. Subsequently, MYC overexpression was achieved by lentiviral transduction, and transduced cells were transplanted into immunodeficient CD1nu/nu recipient mice. Preliminary results show tumor formation in 5/19 transplanted mice (26 %) after 6 months. SMARCA4 loss in all tumor cells was confirmed both immunohistochemically and on a genetic level and suggests a dependency of tumor growth on SMARCA4 loss. In a next step, additional cohorts will clarify if tumor development is accelerated by or even dependent on the loss of SMARCA4 in our model. Additionally, the neoplastic potential of tumor cells will be verified with the aid of secondary recipient mice. To evaluate to what extent the generated tumors are comparable to human Group 3 medulloblastomas, tumors will be extensively analyzed on a morphological, transcriptional, and epigenetic level. Altogether, we hope to establish a suitable mouse model for SMARCA4 mutated Group 3 medulloblastoma that will help to elucidate the role of SMARCA4 in tumor development and to identify new therapeutic targets.